Interferon regulatory factor 8 functions as a tumor suppressor in renal cell carcinoma and its promoter methylation is associated with patient poor prognosis

Zhang, Qian; Li, Li Li; Wang, Zhaohui; Ying, Jianming; Fan, Yu; Xu, Ben; Wang, Lu; Liu, Qianling; Chen, Guangfu; Tao, Qian; Jin, Jie

doi:10.1016/j.canlet.2014.07.040

Cited by 39 publications

(56 citation statements)

References 36 publications

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“…41 After that, several studies verified the regulation of Irf8 expression by DNA methylation. 42, 44, 54 In the present study, we showed hypomethylation in Irf8 at its 5′UTR during cisplatin treatment (Figure 6A), which was associated with Irf8 induction (Figure 6B and 6C). Previously, Irf8 was thought to be exclusively expressed in myeloid and lymphoid cells, 55, 56 but recently it has been found that Irf8 is expressed in a variety of cell and tissue types, such as kidney, liver, lung, and colon.…”

Section: Discussionsupporting

confidence: 61%

“…Previously, Irf8 was thought to be exclusively expressed in myeloid and lymphoid cells, 55, 56 but recently it has been found that Irf8 is expressed in a variety of cell and tissue types, such as kidney, liver, lung, and colon. 44 We also detected Irf8 expression in mouse kidney and rat proximal tubular cells. Under control condition, Irf8 was expressed at a low level, but after cisplatin treatment, Irf8 was induced markedly (Figure 6C and 6D).…”

Section: Discussionmentioning

confidence: 66%

“…Among these genes, interferon regulatory factor 8 (Irf8) stood out as a good candidate gene for further study, because Irf8 is a pro-apoptotic gene that is regulated by DNA methylation. 41-44 In our genome-wide DNA methylation analysis, Irf8 was found to contain a DMR at 5′ UTR region with hypomethylation when mice were challenged with cisplatin (Figure 6A). Real-time PCR analysis indicated that, along with Irf8 hypomethylation, cisplatin induced Irf8 expression (Figure 6B).…”

Section: Resultsmentioning

confidence: 96%

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DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8

Guo

Pei

Xiao

et al. 2017

Kidney International

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DNA methylation is an epigenetic mechanism that regulates gene transcription without changing primary nucleotide sequences. In mammals, DNA methylation involves the covalent addition of a methyl group to the 5-carbon position of cytosine by DNA methyltransferases (DNMTs). The change of DNA methylation and its pathological role in acute kidney injury (AKI) remain largely unknown. Here, we analyzed genome-wide DNA methylation during cisplatin-induced AKI by reduced representation bisulfite sequencing. This technique identified 215 differentially methylated regions between the kidneys of control and cisplatin-treated animals. While most of the differentially methylated regions were in the intergenic, intronic and coding DNA sequences, some were located in the promoter or promoter regulatory regions of 15 protein-coding genes. To determine the pathological role of DNA methylation, we initially examined the effects of DNA methylation inhibitor 5-Aza-2′-deoxycytidine and showed it increased cisplatin-induced apoptosis in a rat kidney proximal tubular cell line. We further established a kidney proximal tubule-specific DNMT1 (PT-DNMT1) knockout mouse model, which showed more severe AKI during cisplatin treatment than wild-type mice. Finally, interferon regulatory factor 8 (Irf8), a pro-apoptotic factor, was identified as a hypomethylated gene in cisplatin-induced AKI and this hypomethylation was associated with a marked induction of Irf8. In the rat kidney proximal tubular cells, knockdown of Irf8 suppressed cisplatin-induced apoptosis, supporting a pro-death role of Irf8 in renal tubular cells. Thus, DNA methylation plays a protective role in cisplatin-induced AKI by regulating specific genes, such as Irf8.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 66%

Section: Resultsmentioning

confidence: 96%

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DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8

Guo

Pei

Xiao

et al. 2017

Kidney International

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“…Its function was verified in renal cancer [22] and breast cancer [23], but its role in the function and mechanisms of NSCLC was unclear. In this study, data revealed that IRF8 was frequently silenced or downregulated in paired cancer tissues compared to adjacent normal tissues, at the mRNA level.…”

Section: Discussionmentioning

confidence: 99%

Interferon Consensus Sequence-Binding Protein 8, a Tumor Suppressor, Suppresses Tumor Growth and Invasion of Non-Small Cell Lung Cancer by Interacting with the Wnt/β-Catenin Pathway

Xiang

Zhu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Interferon consensus sequence-binding protein 8 (IRF8) belongs to a family of interferon (IFN) regulatory factors that modulates various important physiological processes including carcinogenesis. As reported by others and our group, IRF8 expression is silenced by DNA methylation in both human solid tumors and hematological malignancies. However, the role of IRF8 in lung carcinoma remains elusive. In this study, we determined IRF8 epigenetic regulation, biological functions, and the signaling pathway involved in non-small cell lung cancer (NSCLC). Methods: IRF8 expression were determined by Q- PCR. MSP and A+T determined promotor methylation. MTS, clonogenic, Transwell assay, Flow cytometry, three-dimensional culture and AO/EB stain verified cell function. In vivo tumorigenesis examed the in vivo effects. By Chip-QPCR, RT-PCR, Western blot and Immunofluorescence staining, the mechanisms were studied. Results: IRF8 was significantly downregulated in lung tumor tissues compared with adjacent non-cancerous tissues. Furthermore, methylation-specific PCR analyses revealed that IRF8 methylation in NSCLC was a common event, and demethylation reagent treatment proved that downregulation of IRF8 was due to its promoter CpG hypermethylation. Clinical data showed that the IRF8 methylation was associated with tumor stage, lymph node metastasis status, patient outcome, and tumor histology. Exogenous expression of IRF8 in the silenced or downregulated lung cancer cell lines A549 and H1299 at least partially restored the sensitivity of lung cancer cells to apoptosis, and arrested cells at the G0/G1 phase. Cell viability, clonogenicity, and cell migration and invasive abilities were strongly inhibited by restored expression of IRF8. A three-dimensional culture system demonstrated that IRF8 changed the cells to a more spherical phenotype. Moreover, ectopic expression of IRF8 enhanced NSCLC chemosensitivity to cisplatin. Furthermore, as verified by Chip-qPCR, immunofluorescence staining, and western blotting, IRF8 bound to the T-cell factor/lymphoid enhancer factor (TCF /LEF) promoter, thus repressing β-catenin nuclear translocation and its activation. IRF8 significantly disrupted the effects of Wnt agonist, bml284, further suggesting its involvement in the Wnt/β-catenin pathway. Conclusion: IRF8 acted as a tumor suppressor gene through the transcriptional repression of β-catenin-TCF/LEF in NSCLC. IRF8 methylation may serve as a potential biomarker in NSCLC prognosis.

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“…Furthermore, IRF8 is primarily expressed in hematopoietic cells and induces anti-leukemic responses by directly controlling cell growth, differentiation, and apoptosis; and by regulating anti-tumor immune responses [123,124]. Additionally, IRF8 inhibits renal cell carcinoma progression by promoting apoptosis and cell cycle arrest at the G2/M phase, and methylation of its promoter is connected with poor prognosis [125]. On the other hand, IRFs that primarily exhibit cancer-promoting functions include IRF2 and IRF4.…”

Section: Article In Pressmentioning

confidence: 99%

The innate immune signaling in cancer and cardiometabolic diseases: Friends or foes?

et al. 2017

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Interferon regulatory factor 8 functions as a tumor suppressor in renal cell carcinoma and its promoter methylation is associated with patient poor prognosis

Cited by 39 publications

References 36 publications

DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8

DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8

Interferon Consensus Sequence-Binding Protein 8, a Tumor Suppressor, Suppresses Tumor Growth and Invasion of Non-Small Cell Lung Cancer by Interacting with the Wnt/β-Catenin Pathway

The innate immune signaling in cancer and cardiometabolic diseases: Friends or foes?

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